Tenatoprazole, or 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]imidazo[4,5-b]pyridine, is described in Patent No. EP 254.588. It belongs to the group of drugs classified under the name of “proton pump inhibitors” (PPIs), which inhibit the secretion of gastric acid and are useful for the treatment of gastric and duodenal peptic ulcers. Because of its relatively long elimination half-life, tenatoprazole can also be used for the treatment of conditions such as gastro-oesophageal reflux, digestive bleeding and dyspepsia, as described in the French patent application No. FR 02.13113.
The first known derivative of this series of PPIs was omeprazole, described in Patent No. EP 005.129, which has the property to inhibit the secretion of gastric acid and is widely employed as an anti-ulcer in human therapeutics.
In addition to omeprazole, other PPIs are now well known and particular mention can be made of rabeprazole, pantoprazole and lansoprazole, which all exhibit structural analogy and belong to the group of pyridinyl-methyl-sulfinyl-benzimidazoles. These compounds are sulfoxides which have an asymmetry at the level of the sulphur atom, and therefore generally take the form of a mixture (racemic mixture or racemate) of two enantiomers.
Different formulations have been proposed in order to improve the properties or the activity of PPIs. In the case of omeprazole, for example, the PCT application WO 01.28558 describes a stable liquid formulation obtained by forming the sodium or potassium salts in situ in solution in polyethylene glycol, by action of a hydroxide on omeprazole. The medicinal product thus formulated can be used in the usual indications of PPIs.
Like omeprazole and other sulfoxides with similar structure, tenatoprazole has an asymmetric structure and may therefore exist in the form of a racemic mixture and in the form of two enantiomers with configurations “R” and “S”, or (+) and (−), respectively.
Recent studies have shown that unexpectedly and unlike all the other PPIs (such as, for example, omeprazole or lansoprazole), tenatoprazole possesses a remarkably long duration of action which is the result of a longer half-life in plasma (approximately seven times longer). Indeed, clinical data have shown that tenatoprazole induces a degree of symptom relief and healing of gastric lesions which is superior to those achieved by other PPIs, and which allows for its effective use in the treatment of diseases and conditions such as, for example, atypical and oesophageal symptoms of gastro-oesophageal reflux, digestive bleeding and dyspepsia.
Studies conducted by the applicant have unexpectedly shown that the (+) and (−) enantiomers of tenatoprazole contribute differently to the properties of tenatoprazole and exhibit significantly different pharmacokinetic properties. Thus, it is possible to isolate these enantiomers and prepare medicinal products with different pharmacokinetic profiles and specific activities. It then becomes possible to use each enantiomer more effectively for the treatment of specific diseases and conditions.